The invention relates generally to labeled molecular imaging agents and more particularly to imaging agents that are taken up by the cells via the cystine/glutamate transporter.
The concept of molecular imaging promises specific contrast enhancement of molecular signatures of pathology and requires targetable biomarkers that are specifically regulated in certain pathological indications. While such a specific molecular contrast agent could have great utility for imaging and diagnosing disease; validation of a truly specific biomarker has proven to be very difficult. Even if an agent to such a specific biomarker is created, the market for such an agent will be limited to the prevalence of this indication. Therefore there is great interest in developing molecular contrast agents that can be utilized to image a variety of pathological indications. Most imaging agents target specific tissue or cell types, or specific therapies, or they degrade rapidly over time. One example of an agent that is directed at broader applications is 18F-fluorodeoxyglucose (FDG) that makes use of the glucose transporter. 18F-FDG is preferentially taken up by cells that have an increased requirement for glucose, and then is trapped inside the cell. FDG can be used clinically for the diagnosis, staging and monitoring of many cancers as well as monitoring metabolism in the heart and brain. 18F-FDG is not a substrate for sodium-dependent glucose transporters found in the kidney tubules, which prevents its renal resorption and enhances clearance
In vivo oxidative stress is recognized as an indicator of cellular stress. Efforts to image this stress have involved imaging animals using electron paramagnetic resonance (EPR). EPR is a technique for detecting unpaired electrons as would occur with the creation of free radicals in oxidative stress. Essentially an agent is used which is considered to be an EPR probe which is sensitive to organ antioxidative activity as a measure of oxidative stress.
Others have looked at using a 13-C-glycine chemical shift MRI to detect glycine uptake and conversion to glutathione in an animal model of chemotherapy treatment of tumors in vivo. Still others, having developed imaging agents to detect apoptotic cells in vivo for monitoring chemotherapy treatment (e.g. labeled Annexin V which is a rather large protein, Aposense by Neurosurvival Technologies which is a family of small molecules which is reported to enter specifically into only apoptotic cells.
Also reported are imaging agents that take advantage of the cellular amino acid transporter (cystine/glutamate antiporter, xc−), which is activated under conditions of cellular oxidative stress. This is described in U.S. patent application Ser. No. 12/430,573 entitled “Labeled Molecular Imaging Agents, Methods of Making and Methods of Use” and filed on Apr. 27, 2009, which is incorporated herein by reference.
It may also be advantageous to exploit the cystine/glutamate antiporter transport mechanism using other substrates which take advantage of the transport mechanism. As such small molecules that compete with cystine for uptake may be good candidates for imaging agents. Furthermore, the competing mechanism may provide information related to the condition of the cell or its tissue related to its metabolism. Therefore the use of labeled molecules that compete with cystine may provide a valuable tool for identifying tumor types used to design effective treatment therapies.